<p>Evaluation of Exertional Ventilatory Parameters Using Oscillometry in COPD</p>

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O R I G I N A L R E S E A R C H

Evaluation of Exertional Ventilatory Parameters

Using Oscillometry in COPD

This article was published in the following Dove Press journal: International Journal of Chronic Obstructive Pulmonary Disease

Yuji Yamamoto Keisuke Miki Takanori Matsuki Kiyoharu Fukushima Yohei Oshitani Hiroyuki Kagawa Kazuyuki Tsujino Kenji Yoshimura Mari Miki Hiroshi Kida

Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, Osaka, Japan

Background:Oscillometry is a tool to measure respiratory impedance that requires minimal

patients’effort. In patients with chronic obstructive pulmonary disease (COPD), the

correla-tion of respiratory impedance at rest with exercorrela-tional ventilatory parameters, including exercise tolerance, has scarcely been reported. In addition, the utility of oscillometric

parameters might differ between the inspiratory and expiratory phases due to airﬂow

obstruction during expiration, but the hypothesis had not been validated. The aim of the present study was to investigate whether oscillometric parameters are associated with exer-tional ventilatory parameters in patients with COPD.

Methods: Fifty-ﬁve subjects with COPD who attended clinics at the National Hospital Organization Osaka Toneyama Medical Center performed spirometry, oscillometry, and cardiopulmonary exercise testing (CPET) within 2 weeks. The correlations between

para-meters of spirometry, oscillometry, and CPET were analyzed using Spearman’s rank

correla-tion coefﬁcient, univariate, and multivariate analyses.

Results: Respiratory reactance had better correlations with the CPET parameters than respiratory resistance. Moreover, inspiratory reactance at rest correlated with the CPET parameters stronger than expiratory reactance. In particular, inspiratory resonant frequency

(Fres-ins) correlated with peak oxygen uptake (rS=−0.549, p<0.01) and dead space to tidal

volume ratio at peak exercise (rS=0.677, p<0.01) and the best predicted expiratory tidal

volume (VTex) at peak exercise of all the oscillometric parameters (rS=−0.679, p<0.01).

However, the correlation between Fres-ins and VT ex at peak exercise became weak in

subjects with severe and very severe COPD during exercise.

Conclusion:Measurement of respiratory reactance is useful for the effortless evaluation of not only exertional ventilatory parameters but exercise tolerance in patients with COPD. The correlation of respiratory impedance with exertional ventilatory parameters can become weak in patients with advanced COPD; thus, the measurement of oscillometry might not be appropriate for evaluating exertional ventilatory parameters of patients with advanced COPD.

Keywords:dyspnea, dynamic hyperinﬂation, airﬂow obstruction, resonant frequency, tidal volume

Introduction

Globally, chronic obstructive pulmonary disease (COPD) is currently the third

leading cause of death and a major cause of morbidity.1 Improving exercise

tolerance or better physical activity would result in the better prognosis in COPD

patients.2Exercise tests, including 6-minute walk testing (6MWT) and

cardiopul-monary exercise testing (CPET), are the gold standard for evaluation of exercise

tolerance.3–5 6MWT is common and easier to perform than CPET, but CPET can

Correspondence: Keisuke Miki Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka 560-8552, Japan

Tel +81-6-6853-2001 Fax +81-6-6853-3127

Email [email protected]

International Journal of Chronic Obstructive Pulmonary Disease

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evaluate exertional ventilatory parameters more

precisely.4,5Often, however, the tests cannot be performed

in patients with dysmobility, making the evaluation of

exertional ventilatory parameters difﬁcult. Therefore,

effortless evaluations of exertional ventilatory parameters are needed in the patients. As methods easy to evaluate exertional ventilatory parameters, pulmonary function tests, including spirometry and oscillometry, might be important.6,7

Oscillometry, which involves measurements of

within-breath changes in respiratory impedance, measures

respiratory resistance (Rrs) and respiratory reactance (Xrs). Rrs represents the sum of airway resistance and

viscous resistance of the lung and thoracic tissue,8 while

Xrs is considered to reﬂect the elastance and inertia of the

respiratory system.9 Measurement of respiratory

impe-dance using oscillometry is less time-consuming and

requires minimal patients’ cooperation.10 In fact,

oscillo-metry can be used to evaluate patients with severely advanced COPD who are unable to perform even

spirometry.10

In patients with COPD, Rrs and resonant frequency (Fres) correlate negatively and Xrs at a lower frequency of oscillation correlates positively with forced expiration

volume in 1 second (FEV1)/forced vital capacity (FVC)

ratio.11Since peripheral airway obstruction becomes more

severe during expiration,12these oscillometric parameters

change dynamically during respiratory cycle. In particular, Rrs becomes higher and Xrs shifts to a more negative

direction in the expiratory phase.13,14 Moreover, when

airﬂow obstruction develops, expiratory ﬂow at a given

lung volume reaches its maximal value despite increasing

expiratory driving pressure; this is called expiratoryﬂow

limitation (EFL).15–17 EFL during exercise promotes

dynamic hyperinﬂation and contributes to a rapid and

shallow breathing pattern.15,18Xrs is normally thought to

reﬂect the elastic and inertial properties of the respiratory

system in patients without EFL.19 In patients with EFL,

however, oscillatory signals cannot pass through the points of airway obstruction and reach the alveoli; thus, Xrs

reﬂects the mechanical properties of airways proximal to

the choke points which are much stiffer than the periphery

and becomes more negative.19

As other pathophysiology in COPD patients,

ventila-tory inefﬁciency during exercise are reported.16,20 In

patients with ventilatory inefﬁciency, dead space to tidal

volume ratio (VD/VT) becomes higher during exercise.20–22

Ventilatory inefﬁciency is one of the components that

affect exercise tolerance in COPD,23 but the correlation

between ventilatory inefﬁciency and oscillometric

para-meters had not been investigated.

The above observations suggest that the utility of oscil-lometric parameters might differ between the inspiratory and expiratory phases. However, the association between each inspiratory and expiratory oscillometric parameter and ventilatory CPET parameters has never been thor-oughly investigated, although the association of

oscillome-try with 6MWT and CPET has been previously

reported.24,25 In addition, the utility of each oscillometric

parameter for evaluating and predicting exertional

ventila-tory parameters, including ventilaventila-tory inefﬁciency and

exercise tolerance, has not been investigated in patients with COPD. The information obtained from oscillometry might be clinically useful for assessing the mechanisms of exercise impairment and the effects of interventions.

The aims of the present study were as follows: (1) to investigate inspiratory and expiratory oscillometric meters that are associated with exertional ventilatory

para-meters in COPD patients; and (2) to conﬁrm the utility of

oscillometry in COPD patients with various airﬂow

obstructions.

Methods

Subjects

A total of 105 patients with COPD who attended clinics at National Hospital Organization Osaka Toneyama Medical Center or participated in several ethically approved research studies on COPD, between August 2015 and July 2019 were screened in the study. The patients were

conﬁrmed to have a FEV1/FVC ratio of <0.70 after using

a bronchodilator and were diagnosed with COPD based on their spirometry, smoking history, and symptoms including chronic cough, sputum, and dyspnea. The patients

there-fore satisﬁed the deﬁnition of the Global Initiative for

Chronic Obstructive Lung Disease (GOLD).26 Only

COPD patients who underwent spirometry, oscillometry, and CPET were included. Their drug regimens were not changed within 4 weeks before the measurements in this study. Patients were excluded if they were not clinically

stable or had exacerbations, deﬁned as increased dyspnea

associated with a change in the quality and quantity of sputum, for at least three months before the present study. Patients were excluded if they had malignant tumors, severe heart disease, or bronchial asthma (ie a history of bronchial asthma, or respiratory symptoms that i) occur

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variably over time and vary in intensity, ii) occur at night or on waking, or iii) are triggered by exercise, including

CPET). The qualiﬁed 55 symptomatic subjects who met

the study criteria [modiﬁed Medical Research Council

(MRC) dyspnea scale≥1] were evaluated using the

exam-inations described in the following sections.

Study Design

The subjects were evaluated using all three evaluation methods, oscillometry, spirometry, and CPET, within, at

most, a 2-week time period when the subjects’ clinical

symptoms were stable. If oscillometry and spirometry were performed on the same day, spirometry was

per-formed after oscillometry. Short-acting β2-agonists were

not used for more than 12 hours before these tests in all subjects. Long-acting antimuscarinic agents (LAMA) and

long-acting β2-agonists (LABA) were not withdrawn

before the measurements of oscillometry, spirometry, and CPET. The Institutional Review Board of National Hospital Organization Osaka Toneyama Medical Center approved the study protocols and chose an opt-out system

to obtain subjects’ informed consent (approval number,

TNH-2,019,037).

Measurement of Respiratory

Impedance Using Oscillometry

Respiratory impedance was measured at rest with broad-band oscillometry using a commercially available device (Mostgraph-01, Chest MI Co, Ltd, Tokyo, Japan). The methods were performed according to the standard

recommendations.8Partitioned (inspiratory and expiratory)

and average oscillometric parameters and were measured.

Differences between inspiratory and expiratory phases (Δ)

were calculated regarding all oscillometric parameters. As indicators of the frequency dependence of Rrs, Rrs at 5 and 20 Hz (R5 and R20, respectively) and the difference between R5 and R20 (R5-R20) were used. In addition, Xrs at 5 Hz (X5), Fres, and a low-frequency reactance area (ALX) were used as indicators of respiratory reactance. Fres indicates the point where Xrs becomes more domi-nated by inertial rather than elastic forces, and ALX is

deﬁned as the integral of X5 to the Fres.

CPET

Symptom-limited exercise tests were performed using an electrically-braked cycle ergometer (CV-1000SS, Lode, Groningen, The Netherlands) using a CPET system

(Marquette CASE series T 2001, GE Healthcare, Tokyo, Japan; Aeromonitor AE 310S, Minato Medical Science

Co, Ltd, Osaka, Japan).5 First, pre-exercise resting

mea-surements were taken after reaching a steady-state period during at least 3 min of breathing through a mask. Next, incremental testing was performed by increasing 10W per 2 minutes. Before commencing the CPET, subjects were asked to put in maximum effort in the exercises performed during CPET. CPET was then performed until exhaustion without further encouragement, especially during exercise. The subjects were asked to maintain a cycle ergometer speed of about 60 rpm. The following CPET parameters

were measured: expiratory tidal volume (VTex), VD/VT,

mean expiratoryﬂow [VTex/expiratory time (Te)],

breath-ing frequency (fR), minute ventilation (V’E), V’E/V’CO2,

inspiratory duty cycle (Ti/Ttot), and oxygen uptake (V’O2).

These data were measured breath-by-breath and collected as 30 s averages at rest, during exercise at 2 min intervals, and at the end of exercise. In addition, dyspnea intensity

(10-point modiﬁed Borg category-ratio scale) was

evalu-ated at rest, at the last 15 s of each exercise stage, and at the end of exercise.

Spirometry

The subjects underwent spirometry using the CHESTAC 8800 spirometer (Chest MI, Inc, Tokyo, Japan) before

CPET according to the recommendations of the

American Thoracic Society.27 Predicted vital capacity

and predicted FEV1were calculated according to the

for-mula developed by the Japanese Respiratory Society.28

Statistical Analysis

The subjects were grouped into the GOLD stage I and II subgroup (Subgroup A) and the GOLD stage III and IV

subgroup (Subgroup B). The Mann–Whitney U-test was

used for comparison of various parameters among the

subgroups. Spearman’s rank correlation coefﬁcient (rS)

and univariate analyses were used for bivariate correlation analysis of the parameters of respiratory impedance and CPET. Multiple stepwise linear regression analysis was performed to detect the variables of oscillometry that

were signiﬁcant determinants of VT ex, VT ex/Te, fR,

V’E, and V’O2. After detecting the most signiﬁcant oscillo-metric determinants, univariate and multivariate analyses were performed for interaction analyses. These statistical analyses were performed using EZR Version 1.38 (based

on R Version 3.5.2 and R commander Version 2.5–1,

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Saitama, Japan).29 In all analyses, p<0.05 was taken to indicate statistical signiﬁcance.

Results

Baseline Characteristics

Among 55 subjects included in the present study, 16 sub-jects were GOLD stage I or II and 39 subsub-jects were GOLD stage III or IV (Table 1). There were no differences between the subgroups in age, body mass index, and smoking history. As for oscillometry, expiratory impe-dance showed wider variation than inspiratory impeimpe-dance (Table 2). Resistance parameters, Fres, and ALX were higher and X5 was more negative in Subgroup B (Table

3 and Figure 1). Thus, respiratory impedance variously

correlated with the severity of airﬂow obstruction.

Regarding CPET (Table 4), V’O2at rest was higher in

Subgroup A (Table 5). At peak exercise, VTex, VTex/Te,

V’E, V’O2, and Ti/Ttot (p<0.01) were higher in Subgroup

A (Table 5). These data showed that Subgroup A had better exercise tolerance than Subgroup B. Moreover,

given that VD/VTat rest and peak exercise was higher in

Subgroup B (Table 5), the results showed ventilatory

inef-ﬁciency and low oxygen uptake during exercise in subjects

with severe airﬂow obstruction. However, no signiﬁcant

difference was observed in fRbetween the two subgroups,

perhaps because of its wide variation (Figure 2). Whilst, fR

correlated positively with VTex/Te and V’Eat peak

exer-cise, but not with VT ex among all subjects

(Supplementary Figure 1).

Table 1Subjects’Baseline Characteristics (n=55)

Age, Years, n 73.49 (5.56) 61–83

Sex, male/female 54/1

BMI, kg m−2 20.9 (3.2) 14.7–25.8

Cigarette smoking, pack years 56.5 (26.5) 11–141 GOLD stage I/II/III/IV, n 6/10/29/10

GOLD category A/B/C/D, n 10/29/0/16 mMRC dyspnea scale 0/1/2/3/4, n 0/10/22/12/11

Medications

LAMA, n 53

LABA, n 43

ICS, n 22

Triple therapy, n 21

Spirometry

FEV1, L 1.24 (0.62) 0.41–3.73

% FEV1, % predicted 47.10 (22.96) 16.7–141.8

FVC, L 3.01 (0.89) 1.24–5.39

% FVC, % predicted 89.4 (23.7) 39.4–159.9 FEV1/FVC, % 40.35 (11.17) 21.2–69.2

VC, L 3.05 (0.81) 1.68–5.31

%VC, % 84.45 (19.73) 48.40–146.30

IC, L 1.92 (0.52) 0.92–3.08

IRV, L 0.96 (0.44) 0.19–1.79

ERV, L 1.13 (0.47) 0.33–2.85

VT, L 0.96 (0.32) 0.29–1.77

Note:Data are presented as the mean (SD) and the minimum and maximum values, unless otherwise stated.

Abbreviations:BMI, body mass index; ERV, expiratory reserve volume; FEV1,

forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroids; IRV, inspiratory reserve volume; LABA, long-acting β2 agonist; LAMA, long-acting muscarinic antagonist; mMRC dyspnea scale, modiﬁed Medical Research Council dyspnea scale; SD, standard deviation; VC, vital capacity; VT, tidal volume.

Table 2 Results of Baseline Respiratory Impedance at Rest (n=55)

R5, cmH2O/L/s

Inspiratory 3.62 (1.30) 1.20–6.96 Expiratory 4.88 (2.19) 1.53–13.83

Average 4.25 (1.64) 1.54–10.04

ΔR5 −1.26 (1.50) −7.59–1.19

R20, cmH2O/L/s

Average 3.03 (0.96) 1.49–6.08

ΔR20 −0.58 (0.91) −3.76–0.77

R5-R20, cmH2O/L/s

Inspiratory 0.89 (0.60) −0.07–2.80 Expiratory 1.56 (0.99) 0.01–5.89

Average 1.23 (0.74) 0.01–3.96

ΔR5-R20 −0.68 (0.71) −3.86–0.52

X5, cmH2O/L/s

Inspiratory −1.29 (0.85) −3.55 -−0.16 Expiratory −3.64 (3.12) −12.56 -−0.08 Average −2.47 (1.89) −7.54 -−0.13

ΔX5 2.36 (2.58) −0.16–10.05

Fres, Hz

Average 17.31 (6.47) 5.74–32.18

ΔFres −5.55 (4.65) −18.51–1.04

ALX, cmH2O/L/s × Hz

Average 21.53 (20.14) 0.46–83.41

ΔALX −24.41 (28.24) −123.78–0.92

Abbreviations:ALX, low-frequency reactance area;Δ, difference between inspira-tory and expirainspira-tory phases; Fres, resonant frequency; R5 and R20, respirainspira-tory system resistance at 5 and 20 Hz, respectively; SD, standard deviation; X5, respira-tory system reactance at 5 Hz.

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Identi

ﬁ

cation of Oscillometric

Parameters That Best Predicted

CPET Parameters

Univariate analyses showed that respiratory resistance at rest hardly correlated with CPET parameters at rest, and

inspiratory reactance at rest correlated with VTex, VTex/Te,

V’E, and V’O2 at rest (Table 6). However, oscillometric

parameters at rest variously correlated with CPET

para-meters at peak exercise except for fR (Table 7 and

Supplementary Table 1). Moreover, VTex, VTex/Te, V’E,

and V’O2showed a stronger correlation with parameters of

reactance than resistance, and all the inspiratory oscillo-metric parameters showed stronger correlation with these CPET parameters than expiratory oscillometric parameters. In addition, multiple stepwise linear regression analysis determined Fres-ins as the parameter with the strongest

correlation with VT ex, VT ex/Te, V’E, and V’O2

(Supplementary Table 2). Therefore, Fres-ins was detected

as the most signiﬁcant determinant of exertional ventilatory

parameters, including exercise tolerance. However, the cor-relation of exertional ventilatory parameters with Fres-ins

was weaker than that with FEV1, which included the

Table 3Results of Baseline Respiratory Impedance at Rest in the Various GOLD Stages (Stages I–IV) (n=55)

Parameter GOLD Stages I, II (n=16) GOLD Stages III, IV (n=39) p

R5, cmH2O/L/s

Inspiratory 2.70 (1.25) 1.20–6.24 4.00 (1.14) 1.96–6.96 **

Expiratory 4.26 (2.88) 1.53–13.83 5.14 (1.83) 2.24–11.82 *

Average 3.48 (2.03) 1.54–10.04 4.57 (1.36) 2.10–9.14 **

ΔR5 −1.56 (1.82) −7.59–0.02 −1.13 (1.36) −5.64–1.19 NS

R20, cmH2O/L/s

Inspiratory 2.18 (0.73) 1.13–4.21 2.97 (0.71) 1.71–4.75 **

Expiratory 3.01 (1.54) 1.44–7.94 3.45 (1.15) 1.78–7.36 NS

Average 2.59 (1.10) 1.49–6.08 3.21 (0.85) 1.75–5.94 **

ΔR20 −0.83 (0.97) −0.37–0.18 −0.48 (0.88) −3.76–0.77 NS

R5-R20, cmH2O/L/s

Inspiratory 0.52 (0.54) −0.07–2.03 1.04 (0.56) 0.25–2.80 **

Expiratory 1.25 (1.38) 0.01–5.89 1.69 (0.77) 0.14–4.46 **

Average 0.89 (0.94) 0.01–3.96 1.04 (0.56) 0.29–3.20 **

ΔR5-R20 −0.73 (0.93) −3.86–0.52 −0.65 (0.62) −2.53–0.42 NS

X5, cmH2O/L/s

Inspiratory −0.69 (0.53) −2.19 -−0.16 −1.53 (0.84) −3.55 -−0.19 **

Expiratory −1.72 (2.85) −11.11 -−0.08 −4.43 (2.90) −12.56 -−0.42 **

Average −1.20 (1.67) −6.65 -−0.13 −2.98 (1.74) −7.54 -−0.49 **

ΔX5 1.03 (2.39) −0.15–8.92 2.90 (2.48) −0.16–10.05 **

Fres, Hz

Inspiratory 9.87 (3.27) 5.91–17.08 16.44 (5.55) 6.58–30.60 **

Expiratory 12.71 (6.37) 5.56–28.20 23.10 (6.20) 10.67–34.28 **

Average 11.29 (4.71) 5.74–22.64 19.77 (5.42) 9.82–32.18 **

ΔFres −2.84 (3.73) −11.12–1.04 −6.65 (4.58) −18.51–0.37 **

ALX, cmH2O/L/s × Hz

Inspiratory 3.30 (3.43) 0.54–13.25 11.79 (9.59) 0.60–42.08 **

Expiratory 13.41 (26.96) 0.29–97.59 42.07 (32.70) 2.04–145.30 **

Average 8.35 (15.09) 0.46–55.42 26.93 (19.58) 1.93–83.41 **

ΔALX −10.11 (23.80) −84.34–0.81 −30.28 (28.08) −123.78–0.92 **

Notes:Data are presented as the mean (SD) and the minimum and maximum values, unless otherwise stated. *and **p<0.05 and p<0.01 by the Mann–WhitneyU-test, respectively.

Abbreviations:ALX, low-frequency reactance area;Δ, difference between inspiratory and expiratory phases; Fres, resonant frequency; GOLD, Global Initiative For Chronic Obstructive Lung Disease; NS, not signiﬁcant; R5 and R20, respiratory system resistance at 5 and 20 Hz, respectively; SD, standard deviation; X5, respiratory system reactance at 5 Hz.

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correlation of FEV1with V’O2(rS=0.823, p<0.01) and that with V’E(rS=0.903, p<0.01) (Table 7).

Analysis Between Fres-Ins at Rest

and CPET Parameters

Comparing CPET parameters at rest with those at peak

exercise, VTex, VTex/Te, V’E, and V’O2showed stronger

correlations with Fres-ins at peak exercise than at rest (Figure 3). Regarding analyses of fRand Fres-ins, statistical signiﬁ -cance was not observed at either rest or at peak exercise.

Moreover, the differences of CPET parameters between at peak exercise and at rest correlated with Fres-ins, including VTex (rS=−0.571, p<0.01), VTex/Te (rS=−0.598, p<0.01), V’E (rS=−0.555, p<0.01), and V’O2 (rS=−0.558, p<0.01).

This indicated the statistically more signiﬁcant difference in

correlation coefﬁcients at peak exercise compared with at

rest during CPET. Therefore, during exercise, the correlation between Fres-ins at rest and CPET parameters became stronger.

In addition, Fres-ins correlated with an index of the ventilatory inefﬁciency: VD/VTat peak exercise (rS=0.677,

Figure 1Inspiratory impedance at rest in the various GOLD stages (stages I–IV) (n=55). (A) Respiratory resistance and GOLD stages at baseline. (B) Respiratory reactance and GOLD stages at baseline. Sixteen subjects were GOLD stage I or II and 39 subjects were GOLD stage III or IV. **p<0.01 by the Mann–WhitneyU-test.

Abbreviations:ALX, low-frequency reactance area; Fres, resonant frequency; GOLD, Global Initiative for Chronic Obstructive Lung Disease; R5 and R20, respiratory system resistance at 5 and 20 Hz, respectively; X5, respiratory system reactance at 5 Hz.

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p<0.01). However, FEV1 correlated with VD/VT at peak

exercise stronger than Fres-ins (rS=−0.715, p<0.01)

(Table 7).

Correlation Between Fres-Ins at

Rest and CPET Parameters at Peak

Exercise

As indicated by the scatter plots of Fres-ins and VTex, VT

ex/Te, V’E, and V’O2(Figure 3), the correlations between

the various parameters can be considered nonlinear and exponential. Therefore, analyses between Fres-ins and the natural logarithms of these CPET parameters were per-formed. Fres-ins correlated negatively and linearly with the natural logarithms of the CPET parameters (Figure 4).

Combined with the results of Figure 1, which indicated

that Fres-ins correlated positively with the GOLD stages, these analyses using logarithmic conversion implied that the correlation between Fres-ins and the CPET parameters becomes weak in advanced stages of COPD.

Discussion

The present study highlights four majorﬁndings regarding

the correlation between respiratory impedance and exer-tional ventilatory parameters: 1) inspiratory rather than expiratory oscillometric parameters correlated with exer-tional ventilatory parameters stronger; 2) Fres-ins at rest correlated with exertional ventilatory parameters and

reﬂected exercise tolerance in COPD subjects; 3)

Fres-ins correlated with ventilatory inefﬁciency during exercise;

and 4) the correlation between respiratory impedance and

Table 4Results of Cardiopulmonary Exercise Testing at Peak Exercise and at Rest (n=55)

At Peak Exercise At Rest

Incremental load testing

VTex, mL 1132 (332) 597–2047 696 (169) 354–1192

VTex/Te, mL/sec 924 (363) 322–2043 370 (90) 175–660

fR, breaths/min 29 (5) 16–40 21 (6) 8–32

V’E, L/min 33.0 (10.6) 14.6–63.9 13.7 (2.5) 6.8–19.1

Ti/Ttot 0.38 (0.08) 0.24–0.68 0.37 (0.07) 0.22–0.62

V’O2, mL/min 711 (236) 313–1218 249 (45) 171–361

VD/VT 0.40 (0.05) 0.31–0.50 0.44 (0.04) 0.38–0.54

V’E/V’CO2 46.6 (7.6) 33.3–72.3 61.6 (8.6) 46.5–81.9

Abbreviations:fR, breathing frequency; SD, standard deviation; Te, expiration time; Ti/Ttot, inspiratory duty cycle; VD, physiological dead space; VD/VT, dead space to tidal

volume ratio; V’E, minute ventilation; V’E/V’CO2, ventilatory equivalent for carbon dioxide; V’O2, oxygen uptake; VT, tidal volume; VTex, expiratory tidal volume; VTex/Te,

mean expiratoryﬂow.

Table 5Results of Cardiopulmonary Exercise Testing (CPET) at Rest and at Peak Exercise in Various GOLD Stages (Stages I–IV) (n=55)

GOLD Stages I, II (n=16) GOLD Stages III, IV (n=39)

At peak exercise At rest At peak exercise At rest

Incremental load testing

VTex, mL 1515 (246)* 1137–2047 739 (145) 488–935 975 (214) 597–1445 679 (177) 354–1192 VTex/Te, mL/sec 1297 (296)* 927–2043 383 (56) 292–467 771 (265) 322–1464 366 (102) 175–660

fR, breath/min 29 (5) 24–40 20 (4) 14–27 29 (5) 16–40 21 (6) 8–32

V’E, L/min 44.1 (8.3)* 33.0–63.9 14.1 (2.0) 10.4–17.6 28.5 (7.9) 14.6–48.3 13.6 (2.8) 6.8–19.1 Ti/Ttot 0.43 (0.06)* 0.35–0.60 0.38 (0.07) 0.30–0.62 0.36 (0.09) 0.24–0.68 0.36 (0.08) 0.22–0.62 V’O2, mL/min 928 (168)* 696–1218 270 (45)* 171–361 622 (201) 313–1214 240 (42) 173–327 VD/VT 0.35 (0.03)* 0.31–0.40 0.42 (0.04)* 0.38–0.49 0.42 (0.04) 0.34–0.50 0.45 (0.04) 0.38–0.54 V’E/V’CO2 44.9 (6.1) 36.0–54.4 59.5 (8.5) 46.5–78.3 47.2 (8.1) 37.0–72.3 62.5 (8.6) 46.6–81.9

Notes:Data are presented as the mean (SD) and the minimum and maximum values, unless otherwise stated. *p<0.05 by the Mann–WhitneyU-test comparing with each CPET parameter of subjects with GOLD stages III and IV.

Abbreviations:CPET, cardiopulmonary exercise testing; fR, breathing frequency; GOLD, Global Initiative for Chronic Obstructive Lung Disease; SD, standard deviation; Te,

expiratory time; Ti/Ttot, inspiratory duty cycle; VD, physiological dead space; VD/VT, dead space to tidal volume ratio; V’E, minute ventilation; V’E/V’CO2, ventilatory

equivalent for carbon dioxide; V’O2, oxygen uptake; VT, tidal volume; VTex, expiratory tidal volume; VTex/Te; mean expiratoryﬂow.

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exertional ventilatory parameters became weak in subjects

with severe airﬂow obstruction. To the best of our

knowl-edge, this is theﬁrst study to evaluate exertional

ventila-tory parameters using respiraventila-tory impedance at rest. In COPD patients, inspiratory reactance at rest, parti-cularly Fres-ins, better correlated with ventilatory para-meters at peak exercise than those at rest. During exercise, due to the combination of decreased elastic recoil pressure and increased airway resistance, patients with

COPD require a longer expiratory time to enable complete

expiration of tidal volume.30 However, the simultaneous

increase in fR results in a short expiratory time, which is

insufﬁcient for COPD patients to exhale their entire tidal

volume due to airﬂow obstruction, leading to dynamic

hyperinﬂation.18 Accordingly, oscillometric parameters

correlate variously with spirometric parameters including

FEV1,31which reﬂects the severity of airﬂow obstruction.

However, oscillometry has not been considered a surrogate

Figure 2Results of cardiopulmonary exercise testing at peak exercise in the various GOLD stages (stages I–IV) (n=55). (A) Expiratory tidal volume at peak exercise in the various GOLD stages. (B) Mean expiratoryﬂow (VTex/Te) at peak exercise in the various GOLD stages. (C) Breathing frequency (fR) at peak exercise in the various GOLD

stages. (D) Minute ventilation (V’E) at peak exercise in the various GOLD stages. (E) Oxygen uptake (V’O2) at peak exercise in the various GOLD stages. **p<0.01 by the Mann–WhitneyU-test.

Abbreviations:fR, breathing frequency; GOLD, Global Initiative for Chronic Obstructive Lung Disease; NS, not signiﬁcant by the Mann–WhitneyU-test; V’E, minute

ventilation; V’O2, oxygen uptake;VTex, expiratory tidal volume;VTex/Te, mean expiratoryﬂow.

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test for spirometry, because these tests do not necessarily evaluate the same breathing conditions and each oscillo-metric parameter reportedly only fairly or moderately

cor-relates with spirometric parameters.31,32 Therefore, the

correlations between oscillometry and exertional ventila-tory parameters also seemed to be moderate. Nevertheless, we assessed the utility of oscillometry because it is parti-cularly useful for assessing the respiratory pathophysiol-ogy of COPD and for evaluating the exertional ventilatory parameters of patients who are unable to perform even spirometry.

This study suggested that inspiratory impedance at rest correlates with exertional ventilatory parameters of CPET better than does expiratory impedance. Inspiratory rather than expiratory oscillometric parameters were reportedly

less variable.7Airways tend to open during inspiration and

the pressure pulses can be transmitted to the periphery, but

airﬂow obstruction during expiration was suggested to

occur with inhomogeneity in the lung.7,33 Hence, the

more variability of expiratory oscillometric parameters

was probably due to the inhomogeneity of airﬂow

obstruction.7In addition, in patients with COPD, loss of

lung elastic recoil causes EFL, and more negative ΔX5

and higher inspiratory X5 were considered to predict the

presence of EFL.19,34,35 Therefore, subjects in Subgroup

B were estimated to have developed EFL compared with Subgroup A subjects (Table 3). Given that the correlation of Fres-ins with CPET parameters became weak in advanced COPD subjects (Figure 4), EFL and/or dynamic

hyperinﬂation might potentially have associated with the

inhomogeneity of airﬂow obstruction. Therefore,

inspira-tory impedance might be a more useful parameter for evaluating exertional ventilatory parameters in patients with COPD. In addition, oscillometry might be useful for

Table 6 Spearman’s Rank Correlation Coefﬁcient Between Parameters of Respiratory Impedance at Rest, Spirometry, and Cardiopulmonary Exercise Testing at Rest (n=55)

VTex VTex/Te fR V’E V’O2 VD/VT

Oscillometry R5

Inspiratory −0.260 NS −0.193 NS 0.236 NS −0.065 NS −0.111 NS 0.175 NS

Expiratory −0.176 NS −0.048 NS 0.222 NS 0.050 NS −0.105 NS 0.108 NS

R20

R5-R20

Expiratory −0.174 NS −0.140 NS 0.182 NS −0.031 NS −0.189 NS 0.094 NS

X5

Inspiratory 0.365 ** 0.246 NS −0.257 NS 0.152 NS 0.289 * −0.338 *

Expiratory 0.143 NS 0.119 NS −0.153 NS −0.005 NS 0.114 NS −0.245 NS

Fres

Inspiratory −0.356 ** −0.278 * 0.241 NS −0.148 NS −0.335 * 0.385 **

Expiratory −0.174 NS −0.194 NS 0.155 NS −0.038 NS −0.220 NS 0.303 *

ALX

Inspiratory −0.372 ** −0.250 NS 0.258 NS −0.155 NS −0.296 * 0.314 *

Spirometry

FVC 0.429 ** 0.503 ** −0.093 NS 0.434 ** 0.506 ** −0.156 NS

FEV1 0.352 ** 0.419 ** −0.136 NS 0.304 * 0.467 ** −0.253 *

FEV1/FVC 0.039 NS 0.131 NS −0.004 NS 0.006 NS 0.143 NS −0.180 NS

Notes:*p<0.05; **p<0.01.

Abbreviations:ALX, low-frequency reactance area; FEV1, forced expiratory volume in 1 second; fR, breathing frequency; Fres, resonant frequency; FVC, forced vital

capacity; NS, not signiﬁcant; R5 and R20, respiratory system resistance at 5 and 20 Hz, respectively; Te, expiratory time; V’E, minute ventilation; V’O2, oxygen uptake; VTex,

expiratory tidal volume; VTex/Te, mean expiratoryﬂow; X5, respiratory system reactance at 5 Hz.

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detecting the inhomogeneity of airﬂow obstruction in COPD. Further investigations are necessary to validate the hypothesis.

The present study indicated that Fres-ins was the best

oscillometric parameter for predicting V’O2 and V’E at

peak exercise. Given the stronger correlation between

Fres-ins at rest and VT ex at peak exercise than that

between Fres-ins at rest and VT ex at rest (Figure 3),

respiratory reactance at rest might correlate with the

degree of VT expansion. Consequently, Fres-ins might

have correlated with V’O2at peak exercise, which is

cal-culated using V’E: the product of VTex and fR. Given that

changes in X5 and Fres related to small airway

broncho-dilation in COPD,36 Fres-ins might have reﬂected airway

obstruction and correlated with VTex. Further studies to

assess the correlation of Fres-ins with VT ex might be

necessary. The present study suggested that respiratory

impedance measured by oscillometry, particularly respira-tory reactance at rest, is useful for evaluating exertional

ventilatory parameters quantitatively and can be

a complementary tool for predicting exercise tolerance, although the utility of oscillometry was not better than that of spirometry.

In addition, the present study suggested that respiratory

reactance correlated with ventilatory inefﬁciency. In

Subgroup B, increased VD/VT at peak exercise showed

ventilatory inefﬁciency during exercise (Table 5). This

was also supported by the prolonged expiratory time and the shallow breathing pattern (Table 5). Moreover, the

correlation between Fres-ins and VD/VT indicated that

Fres-ins might be used as a surrogate marker for

ventila-tory inefﬁciency during exercise because VD/VT is

a common marker of ventilatory inefﬁciency.16,20

Fres-ins might potentially be useful as an index easy to measure

Table 7 Spearman’s Rank Correlation Coefﬁcient Between Parameters of Respiratory Impedance at Rest, Spirometry, and Cardiopulmonary Exercise Testing at Peak Exercise (n=55)

VTex VTex/Te fR V’E V’O2 VD/VT

Oscillometry R5

Inspiratory −0.560 ** −0.487 ** 0.111 NS −0.491 ** −0.404 ** 0.480 **

Expiratory −0.413 ** −0.329 ** 0.063 NS −0.388 ** −0.322 * 0.358 **

R20

Inspiratory −0.490 ** −0.426 ** 0.113 NS −0.438 ** −0.327 * 0.384 **

Expiratory −0.297 * −0.241 NS 0.020 NS −0.309 * −0.207 NS 0.252 NS

R5-R20

Inspiratory −0.558 ** −0.459 ** 0.136 NS −0.457 ** −0.432 ** 0.510 **

Expiratory −0.522 ** −0.427 ** 0.063 NS −0.486 ** −0.439 ** 0.422 **

X5

Inspiratory 0.631 ** 0.537 ** −0.163 NS 0.520 ** 0.516 ** −0.620 **

Expiratory 0.488 ** 0.446 ** −0.049 NS 0.463 ** 0.419 ** −0.463 **

Fres

Inspiratory −0.676 ** −0.586 ** 0.138 NS −0.566 ** −0.568 ** 0.677 **

Expiratory −0.577 ** −0.533 ** 0.027 NS −0.564 ** −0.514 ** 0.554 **

ALX

Inspiratory −0.658 ** −0.553 ** 0.155 NS −0.541 ** −0.537 ** 0.607 **

Expiratory −0.517 ** −0.463 ** 0.057 NS −0.489 ** −0.445 ** 0.437 **

Spirometry

FVC 0.770 ** 0.798 ** 0.115 NS 0.756 ** 0.718 ** −0.550 **

FEV1 0.875 ** 0.871 ** 0.155 NS 0.903 ** 0.823 ** −0.715 **

FEV1/FVC 0.496 ** 0.477 ** 0.168 NS 0.556 ** 0.470 ** −0.453 **

Notes:*p<0.05; **p<0.01.

Abbreviations:ALX, low-frequency reactance area; fR, breathing frequency; FEV1, forced expiratory volume in 1 second; Fres, resonant frequency; FVC, forced vital

capacity; NS, not signiﬁcant; R5 and R20, respiratory system resistance at 5 and 20 Hz, respectively; Te, expiratory time; V’E, minute ventilation; V’O2, oxygen uptake; VTex,

expiratory tidal volume; VTex/Te, mean expiratoryﬂow; X5, respiratory system reactance at 5 Hz.

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for adding or choosing interventions to improve

ventila-tory inefﬁciency in patients with COPD, although further

studies are needed.37 The present studyﬁrst showed that

oscillometric parameters correlated with ventilatory inefﬁ

-ciency during exercise and indicated the potential role of respiratory impedance for effortlessly assessing exertional ventilatory parameters qualitatively in COPD patients.

The correlation between respiratory impedance and exertional ventilatory parameters can become weak in

patients with advanced COPD. In the present study, the

more reducedVTex/Te in Subgroup B implied that airﬂow

obstruction during exercise became more severe (Table 5). Moreover, as described above, subjects in Subgroup B were estimated to have developed more severe EFL than those in Subgroup A. In addition, the exponential correlations between Fres-ins at rest and CPET parameters at peak exercise showed that the correlations between oscillometry and CPET became weak in COPD subjects

Figure 3Results of univariate analyses and Spearman’s rank correlation coefﬁcient analyses between inspiratory resonant frequency (Fres-ins) at rest and ventilatory parameters of cardiopulmonary exercise testing (CPET) (n=55). In eachﬁgure, the graphs on the left show the results of Fres-ins at rest and CPET ventilatory parameters at peak exercise, while those on the right show the results of Fres-ins at rest and ventilatory parameters at rest, respectively. (A) Fres-ins and expiratory tidal volume (VTex).

(B) Fres-ins and mean expiratoryﬂow (VTex/Te). (C) Fres-ins and breathing frequency (fR). (D) Fres-ins and minute ventilation (V’E). (E) Fres-ins and oxygen uptake (V’O2).

*p<0.05; **p<0.01.

Abbreviations:CPET, cardiopulmonary exercise testing; fR, breathing frequency; Fres-ins, inspiratory resonant frequency; NS, not signiﬁcant; R 2

, R-squared; rS, Spearman’s

rank correlation coefﬁcient; stdβ, standardized regression coefﬁcient estimate; V’E, minute ventilation; V’O2, oxygen uptake; VTex, expiratory tidal volume; VTex/Te, mean

expiratoryﬂow.

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with severe airﬂow obstruction (Figure 4). Given these results, oscillometry might not be appropriate for evaluat-ing exertional ventilatory parameters in advanced COPD patients with EFL because wide variations in respiratory reactance level at rest decrease the accuracy of evaluation. The present study included a small number of subjects and was a single-center study; thus, further investigations are

needed to validate the hypothesis and to verify the clinical utility of oscillometry in patients with advanced COPD.

The present study had some limitations. First, it was a single-center investigation and some selection bias might

have affected the ﬁndings. Second, this study included

a small number of subjects. In particular, only one female subject was included in the study. In addition, the number

Figure 4Results of Spearman’s rank correlation coefﬁcient and univariate analyses of the correlation between inspiratory resonant frequency (Fres-ins) at rest and ventilatory parameters of cardiopulmonary exercise testing (CPET) at peak exercise (n=55).Interaction analyses were performed for Fres-ins and natural logarithms of exertional ventilatory parameters of CPET. All the analyses were statistically signiﬁcant (p<0.01). (A) Fres-ins and expiratory tidal volume (VTex). (B) Fres-ins and mean

expiratoryﬂow (VTex/Te). (C) Fres-ins and minute ventilation (V’E). (D) Fres-ins and oxygen uptake (V’O2).

Abbreviations:β, unstandardized regression coefﬁcient estimate; CPET, cardiopulmonary exercise testing; Fres-ins, inspiratory resonant frequency; R2, R-squared; V’E, minute ventilation; V’O2, oxygen uptake; VTex, expiratory tidal volume; VTex/Te, mean expiratoryﬂow.

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of COPD subjects with each GOLD stage was small. Hence, a larger study population is required to validate the results. Third, this study did not include a healthy control group because only symptomatic subjects who underwent oscillometry, spirometry, and CPET were eval-uated retrospectively.

In conclusion, respiratory reactance at rest, particularly Fres-ins, was able to estimate exertional ventilatory para-meters of CPET. Inspiratory reactance is useful for effort-lessly predicting exertional ventilatory parameters both quantitatively and qualitatively in patients with COPD, but oscillometry might not be appropriate to evaluate exertional ventilatory parameters in patients with advanced COPD with EFL. Further investigations of oscillometry to accurately evaluate exertional ventilatory parameters and to improve the clinical utility are necessary.

Abbreviations

ALX, low-frequency reactance area; β, unstandardized

regression coefﬁcient estimate; BMI, body mass index;

COPD, chronic obstructive pulmonary disease; CPET,

car-diopulmonary exercise testing; Δ, difference between

inspiratory and expiratory phases; ERV, expiratory reserve

volume; FEV1, forced expiratory volume in 1 second; fR,

breathing frequency; Fres, resonant frequency; Fres-ins inspiratory resonant frequency; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticoster-oids; IRV, inspiratory reserve volume; LABA, long-acting

β2-agonists; LAMA, long-acting muscarinic antagonists;

R2, R-squared; R20, respiratory resistance (Rrs) at 20

Hz; R5, Rrs at 5 Hz; R5-R20, difference between R5 and

R20; Rrs, respiratory resistance; rS, Spearman’s rank

cor-relation coefﬁcient; SD, standard deviation; stdβ,

standar-dized regression coefﬁcient estimate; Te, expiratory time;

Ti/Ttot, inspiratory duty cycle; VC, vital capacity; VD,

physiological dead space; VD/VT, dead space to tidal

volume ratio; V’E, minute ventilation; V’E/V’CO2,

ventila-tory equivalent for carbon dioxide; V’O2, oxygen uptake;

VT, tidal volume; VTex, expiratory tidal volume; VTex/

Te, mean expiratory ﬂow; X5, respiratory reactance (Xrs)

at 5 Hz; X5-ins, inspiratory X5; Xrs, respiratory reactance.

Data Sharing Statement

All data generated or analyzed during this study are

included in this published article and its supplementary

material ﬁle.

Ethics Approval and Consent to

Participate

The present study was conducted according to the princi-ples of the Declaration of Helsinki and was approved by the ethics committee of NHO Osaka Toneyama Medical

Center (approval number, TNH-2,019,037). The

Institutional Review Board of NHO Osaka Toneyama

Medical Center chose an opt-out system to obtain subjects’

informed consent.

Acknowledgments

The authors would like to thank Ms S Ito, Ms S Sakaguchi and Mr T Uenishi for their help with the CPET measurements.

Author Contributions

YY contributed to conceptualizing and designing the study, data collection and analysis, and wrote the manu-script. KM cared for all the subjects, contributed to con-ceptualizing and designing the study, data analyses, and revision of the manuscript. TM, KF, YO, HK, KT, and KY contributed to collecting subject data and revising the manuscript. MM and HK contributed to data interpretation and design of the study. All the authors reviewed and

approved the submission of theﬁnal manuscript.

Funding

The authors received no speciﬁc funding for the present

study.

Disclosure

The authors declare no conﬂicts of interest in association

with the present study.

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